Abstract Bone marrow hematopoietic stem and progenitor cells (BM HSPCs) express innate immune sensors for bacterial products including toll-like receptor 4 (TLR4). Unexpectedly, we recently demonstrated in a non- infectious setting that HSCs from TLR4 signaling deficient mice outcompete wild-type in competitive adoptive transfer. These findings open a new avenue of investigation into the role of basal TLR4 signals in steady-state hematopoiesis. Further, these observations raise questions about BM corruption in disease conditions marked by increased levels of circulating TLR4 ligands. In Aim 1, we will use genome-wide approaches to determine the transcriptome and chromatin structure of TLR4-deficient versus -sufficient HSCs, an essential step toward identifying the molecular basis of functional changes. Aim 2, we will perform separation-of-function experiments to distinguish the mechanistic importance of two distinct co-receptors, CD14 (LPS) versus Fetuin A (saturated fats), to TLR4-dependent HSPC lymphoid suppression in obesity, a disease of global burden. The outcomes of these studies will significantly advance our understanding of how environmental cues delivered through a hallmark innate immune sensor shape BM hematopoietic processes.